96. Jahrestagung der Deutschen Gesellschaft für Pathologie e. V ...

SO-068
Recent advances in understanding the genetic and epigenetic
networks of germ cell tumors
D . Nettersheim 1 , B . Westernstroer 2 , S . Schlatt 2 , H . Schorle 1
1 University of Bonn Medical School, Institute of Pathology, Bonn,
2 University of Münster, CERA, Münster
Aims. In the past decades the incidence of germ cell tumors (GCT) has
been rising constantly. It is believed, that GCT arise from an arrested
progenitor to form an IGCNU (CIS). With puberty, CIS eventually progress
into seminoma and nonseminoma. The genetics of this progression
is poorly understood, so knowledge of genetic and epigenetic markers
is mandatory. Further, the establishment of a murine model system for
CIS/seminoma and embryonal carcinoma would further help in addressing
functional questions relating to GCT initiation, progression and
treatment.
Methods. We used cell lines derived from seminoma (TCam-2) and embryonal
carcinoma (2102EP) as well as paraffin sections from human fetal
material and germ cell tumors to elucidate the specificity of the markers
for primordial germ cells BLIMP1, PRMT5 and TFAP2C. Furthermore,
we generated knock down cell lines as well as knockout-models for
TCFAP2C in order to analyze the requirement of these factors. Finally,
we transplanted various GTC cell lines to nude mice and analyzed tumor
initiation and development.
Results. In our hands, the markers BLIMP1 and TFAP2C are highly
specific for CIS and seminoma. They are downregulated in embryonal
carcinoma, forced loss of these factors leads to upregulation of somatic
marker genes indicative for differentiation. A lack of Tfap2c in the murine
model results in sterility. Transplantation of the TCam2 seminoma
cell line revealed, that this cells grew as CIS/seminoma or embryonal
carcinoma depending on the microenvironment.
Conclusions. We demonstrate that TFAP2C and BLIMP1 might be suitable
for the diagnostics of GCTs. We show that these proteins are required
for the maintenance of the undifferentiated status of CIS and seminoma.
Finally, the establishment of a murine model for GCT enables for in vivo
studies relating to germ cell tumor biology.
SO-069
Progressive kidney lesions in mutant mouse models for uromodulin-associated
kidney disease
E . Kemter1 , S . Sklenak 1 , P . Prueckl1 , B . Rathkolb 1 , F . Habermann2 , M . Hrabé de
Angelis3 , E . Wolf1 , B . Aigner1 , R . Wanke 4
1LMU Munich, Chair for Molecular Animal Breeding and Biotechnology,
München, 2LMU Munich, Chair for Veterinary Anatomy, Histology, and
Embryology, Department of Veterinary Sciences, München, 3Helmholtz Zentrum München, Institute of Experimental Genetics, Neuherberg, 4LMU Munich, Institute of Veterinary Pathology, Center for Clinical Veterinary
Medicine, München
Aims. Uromodulin-associated kidney disease (UAKD) is a heritable renal
disease in humans caused by mutations in the uromodulin (UMOD)
gene. Impaired maturation of mutant uromodulin with retention of
uromodulin in the hyperplastic endoplamic reticulum is considered to
be causative for thick ascending limb (TALH) cell dysfunction. Besides
clinical symptoms like hyperuricemia, gout, and alteration of urine concentrating
ability, histological kidney alterations like tubulointerstitial
nephritis, cysts, and interstitial fibrosis are heterogeneously present in
affected humans. Progression of disease leading to end-stage-kidney
disease is a feature of UAKD, which pathophysiology is unknown. The
objective of this study was to analyze the age-associated development of
kidney alterations of two recently described mutant mouse lines carrying
two different Umod mutations.
Methods. Histopathology, immunohistochemistry, confocal laser scanning
microscopy, quantitative stereology, and transmission electron microscopy.
Results. Both the kind of uromodulin mutation and the allelic status
influence onset, severity, and progression of renal dysfunction, as demonstrated
by a continuous age-related increase of plasma urea concentrations
in mutant mice. Interstitial fibrosis and tubular atrophy (IFTA)
as well as interstitial infiltrates of inflammatory cells were constantly
present in kidneys of aged mutant mice of both lines. An association of
different Umod mutations and allelic status with differences in onset,
degree, and progression of these nephropathological alterations was detected.
Further, glomerulocystic and tubulocystic changes were occasionally
observed in kidneys of aged mutant mice.
Conclusions. Both Umod mutant mouse lines represent valuable models
for human UAKD and enable insights into the pathogenesis of this disease.
Intracellular accumulation and release of mutated uromodulin
might trigger an inflammatory response leading to interstitial fibrosis.
Intracellular accumulation of the mutated misfolded protein in the hyperplastic
ER might lead to TALH cell death leading to tubular atrophy.
Supported by the German Research Foundation (KE1673/1-1) .
AG Urologische Pathologie II
SO-071
Renal cell carcinoma – Implications for cooperation of pathologists
and urologists
T . Steiner 1
1HELIOS hospital Erfurt, Erfurt
Aims. Over the last ten years various new options have been developed
for the management of patients with renal cell carcinoma (RCC).
Methods. Due to improved imaging techniques small renal masses
(SRM) are detected more frequently. About 20% of renoparenchymal
tumors with less then 3 cm in diameter have benign histology. Despite
RCC histology a significant amount of the remaining tumors show
only minimal growth over time. Therefore, in elderly patients or those
with significant comorbidities active surveillance strategies should be
considered. Renal mass biopsy enhanced by molecular profiling holds
promise for assessing aggressive potential in this scenarium. Histologic
subtypes and genetic aberrations of RCC predict different probability of
development of local recurrence, lymph node and distant metastases and
should be considered in follow up after local surgery for RCC.
Results. The development of targeted therapy revolutionized the management
of metastatic RCC. It was based on the detection of VHL mutations
with consecutive expression of growth factors in clear cell RCC.
For other histologic RCC subtypes VEGF targeted therapy seems to be
less effective. But even in clear cell RCC primary and secondary resistance
occurs. In the future predictive molecular markers have to be determined
to give patients a chance of really individualized medicine.
Conclusions. In conclusion, cooperation between urologists and pathologists
is of increasing meaning for optimal management of RCC.
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